overview of human genetics - arizona state universityjtaylor/teaching/spring2014/mat...overview of...

Overview of Human Genetics

1 Structure and function of nucleicacids.

2 Structure and composition of thehuman genome.

3 Mendelian genetics.

Lander et al. (Nature, 2001)

MAT 394 (ASU) Human Genetics Spring 2012 1 / 27

Nucleic Acid Structure

DNA and RNA are polymers of nucleotides

Nucleotides have three components:

a 5-carbon sugar: deoxyribose(DNA) or ribose (RNA)

1-3 phosphate groups linked tothe 5’ carbon of the sugar

a nitrogenous base linked tothe 1’ carbon of the sugar



Nucleic Acid Sugars

Deoxyribose contains one less hydroxyl (-OH) group than ribose.

The carbons are numbered clockwise 1’-5’.



Five Nitrogenous Bases

A, T, C, G in DNA

A, U, C, G in RNA



Nucleotides polymerize by forming phosphodiester bonds

Polymerization proceeds 5’ to 3’: RNAand DNA molecules grow by adding newnucleotides at the 3’ end.

Nucleic acids are oriented and byconvention sequences are always written5’ to 3’. Thus, ATTGCA 6= ACGTTA.

The addition of new nucleotides iscatalyzed by a polymerase.

Nucleotides can be removed by nucleases.



Pyrimidine-purine base pairs form by hydrogen bonding

A-T and G-C base pairs have similardimensions (∼ 2 nm).

G-C base pairs have three H-bondsand are more stable than A-T basepairs.

A-U base pairs can form in RNA.



Base pairing allows complementary strands to hybridize

Hybridization occurs spontaneouslybetween complementary ssDNAunder physiological conditions.

Strands are anti-parallel, e.g.,ATTGCA is complementary toTGCAAT.

Hybridized strands ‘melt’(disassociate) at high temperatures.

Key to replication and transcriptionof DNA and to many technologies:PCR, microarrays.



Complementary DNA strands form a double helix



dsDNA wraps around histone octamers to form nucleosomes

The core nucleosome consists of:

histone octamer: two copiesof H2A, H2B, H3, H4

147 bp DNA wrapped in1.67 turns

50-70 bp of linker DNAbetween nucleosomes

Histones are highly conserved, positively-charged, and have tail domainsthat can be acetylated and methylated, affecting gene expression.



DNA is highly compactedwith several levels oforganization.

Length of humangenome is ∼ 2m(outstretched)

Diameter of nucleus is∼ 6µm



Topography of a chromosome

Chromosomes have two arms, separatedby a region known as the centromere.

The p-arm is the smaller of the twoarms; the q-arm is the larger.

Chromosome ends are called telomeres.

Certain dyes can be used to reveala characteristic banding structure for eachchromosome which depends on howcondensed the chromatin is.

These bands provide landmarks relativeto which the locations of other features(genes, polymorphic markers) can be specified.

human chromosome 10



RNA is usually single stranded with intra-strand helices


Nucleic Acid Functions Replication

DNA replication is semiconservative

Each copy contains one of the original strands and one new strand.


Nucleic Acid Functions Protein synthesis

The Central Dogma of Molecular Biology



The Genetic Code is Degenerate

20 amino acids

4 nucleotides

43 = 64 codons

1 start codon (AUG)

3 stop codons

third position isoften degenerate



Eukaryotic genes contain coding and non-coding segments

Introns are removed from the precursor mRNA.


Structure of the Human Genome

The Human Karyotype

Most human cells are diploidwith 23 pairs of chromosomes.

22 pairs of autosomes

X, Y sex chromosomes

Exceptions: gametes arehaploid and have 23chromosomes; red bloodcells lack nuclei altogether.



Sex Chromosomes

Sex determination in humans is chromosomal: XX individuals arefemale and XY individuals are male (usually).

Humans are female by default: the presence of a particular Y-linkedgene (SRY) is necessary and sufficient for development as a male.

XXY and XYY individuals are male; XO and XXX individuals arefemale.

There are rare instances of XY females due to inactivating mutationsin the SRY gene.

The X-chromosome is 155 mb long and contains about 1, 846 genes.

The Y-chromosome is 58 mb long and contains about 80 genes.



Contents of the Human Genome

3 billion base pairs per haploidcomplement

23, 000 protein-coding genes:exons (2%), introns (24%)

transposable elements (51%)can move around the genomeand many can replicate

satellite DNA (6%) consists ofnon-coding tandem repeats

Rollins et al. (Genome Research, 2006)



Mitochondria also have genomes

Human mt genome:

circular

16569 bp

13 protein-coding genes

12S and 16S rRNA genes

22 tRNA genes

maternally-inherited

Mitochondria are sub-cellular organelles where ATP is produced. Humancells contain 10’s to 1000’s mitochondria per cell.


Mendelian Genetics

Mitosis, Meiosis and Mendelian Genetics

Eukaryotic cells can divide by two processes.

Mitosis is the process by which diploid somatic cells divide in two.Apart from mutation, the daughter cells are genetically identical tothe parent.

Meiosis is the process by which diploid germ cells produce haploidgametes. This involves one round of DNA duplication, two roundsof cell division, and results in the production of four gametes.

Mendelian genetics (Mendel, 1866) explains how offspring inheritgenomes and traits from their parents.


Mendelian Genetics

Mendel’s Law of Segregation

An individual carries two copies ofeach locus called alleles.

Homozygotes have two identicalalleles (RR); heterozygotes havetwo different alleles (Rw).

Each parent transmits just one ofthese two alleles to its offspring.

Both copies are equally likely to betransmitted (usually).

Usually, the sex of the parent contributing an allele doesn’t matter, so thatRw and wR heterozygotes are indistinguishable. Genomic imprinting isan exception, affecting expression of about 80 human genes.


Mendelian Genetics

Mendel’s Law of Independent Assortment

Different chromosomes segregateindependently.

Loci on the same chromosomeare usually inherited together,but can be reshuffled byrecombination.

Gametic phase cannot bedirectly inferred from singlelocus genotypes: an AaBbdouble heterozygote couldbe AB/ab or Ab/aB.


Mendelian Genetics

Crossing over during meiosis I produces recombinant gametes.


Mendelian Genetics

Recombination Rates

Recombination (usually) occurs only between homologouschromosomes.

Each pair of homologs undergoes at least one crossover duringmeiosis, but multiple crossovers can also occur.

The probability that two loci recombine is an increasing function ofthe physical distance (number of basepairs) between them.


Mendelian Genetics

Non-recombining Markers

The mitochondrion is maternally inherited andso its genome does not recombine.

Most of the Y chromosome is non-recombining,except for two short terminal regions thatrecombine with the X (pseudo-autosomalregions).

Recombination occurs along the entire lengthof the X chromosome in females.

Non-recombining loci share the same genealogy,e.g., the entire mtDNA genome has a singlegenealogical history.


Mendelian Genetics

References

Alberts, B. et al. (2007) Molecular Biology of the Cell. 5’th edition.Garland Science.

Krebs, J. E., Goldstein, E. S. and Kilpatrick, S. T. (2011) Lewin’sGenes X. Jones and Bartlett.

Sturtevant, A. H. and Lewis, E. B. (2001) A History of Genetics. ColdSpring Harbor Laboratory.


overview of human genetics - arizona state universityjtaylor/teaching/spring2014/mat...overview of...

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